CD4 T cells are central for eradicating many pathogens. However, immune stimulatory pathways are dysregulated during chronic viral infections preventing timely CD4 T cell immunity. Human persistent viruses, including human immunodeficiency virus (HIV), hepatitis C and B viruses (HCV and HBV) and human cytomegalovirus (HCMV) cause tremendous disease burden worldwide but are restricted to human and nonhuman primates, which in turn poses great limitations for experimental-based research. Importantly, studies over the past three decades with lymphocytic choriomeningitis virus (LCMV) and murine CMV (MCMV) infections in their natural rodent hosts indicate that they are widely applicable to model immune responses against persistent viruses in humans. We have used chronic lymphocytic choriomeningitis virus (LCMV) infection in its natural host, the mouse, as a model system for persistent infections with continuous viral replication. We found that interleukin-6 (IL-6) and IL-27 are essential for optimal CD4 T cell differentiation into T follicular helper cells (Tfh) and CD4 T cell survival, respectively, while they redundantly induce IL-21 production at late (but not early) stages of infection. Importantly, both IL-6 and IL-27 were absolutely required to control chronic (but not acute) LCMV infection (Harker et al. Science 2011 and Immunity 2013). Strikingly, new preliminary data suggest that while IL-6 operates similarly in LCMV and MCMV infections, IL-27 is not necessary for survival of MCMV-specific CD4 T cells and instead suppresses the differentiation of granzyme A producing and KLRG1+EOMEShigh (putative cytotoxic) MCMV-specific CD4 T cells, which frequency correlates with MCMV control. Consistently, IL-27 appears to promote (rather than restrain) MCMV persistence and latent loads. The overall goal of the current proposal is to fully dissect the mechanisms underlying IL-6 and IL-27 induction as well as their regulation of CD4 T cell responses during chronic infection with a continuously replicating virus (LCMV) and to further investigate their roles during infection with a virus that establishes latency (MCMV). To accomplish this goal, we propose in aim #1 to investigate the induction of IL-6 and IL-27 production (including cellular sources and upstream signaling pathways) throughout chronic LCMV infection. In aim #2, we plan to study the molecular mechanisms of IL-6 and IL-27 downstream signaling pathways, STAT targeting and epigenetic status of Tfh-related and IL-21 gene promoters and the role of potential STAT co- regulators in shaping CD4 T cell responses early vs. late after chronic LCMV infection. Lastly, in aim #3 we will evaluate the role of IL-6 an IL-27 signaling in CD4 T cells during chronic MCMV infection and investigate their relevant time of action, cellular source as well as the significance and mechanisms underlying IL-27 suppression of MCMV-specific KLRG1+EOMEShigh (putative cytotoxic) CD4 T cells that prominently appear during MCMV (but not LCMV) infection. The knowledge gained from the proposed experiments will not only enhance our understanding of the basic biology of key immune players (i.e. IL-6, IL-27 and CD4 T cells) but may also provide valuable information for therapeutically manipulating the aforementioned cytokines during chronic viral infections and potentially CMV-based vaccination.